It is proposed to investigate three major intertwined areas related to MSH and the hormones which control its release. Previous work on this project involving the application of endocrinological ideas to the brain has resulted in promising results in some neurological and mental diseases. Earlier work on this project has established the inhibitory influence of substance present in hypothalamic tissue upon release of melanocyte-stimulating hormone (MSH) from the pituitary. The chemical structure of this substance or substances remains to be clarified. First, it is proposed to determine the identity of this MSH-release inhibiting factor (MIF) as well as releasers of MSH from the pituitary. Secondly, the extra-pigmentary effects of MSH upon the central nervous system (CNS) will be further investigated. In particular, several behavioral effects will be studied in an attempt to better define the CNS effects of MSH, particularly now that its clinical effects have been observed in mentally retarded men. The thorough study of MSH should yield results applicable to other peptide-hormones. Thirdly, it appears from work done previously on this project that a small peptide found in the hypothalamus with MIF activity has direct effects upon the brain which do not require the presence of the pituitary gland. This MIF tripeptide, Pro-Leu-Gly-NH2, is active in several systems which some investigators consider animal models of parkinsonism and mental depression and has been found in several clinical studies based on the animal work to alleviate the symptoms of Parkinson's disease. It is proposed to continued these investigations and determine the mechanism by which these effects are exerted upon the central nervous system. The study of MSH and MIF-I on brain melanin, usually absent from some brain regions in Parkinson's disease, emphasizes the interrelations of the three parts of the proposal. IDEN*